Sexually dimorphic impact of the iron-regulating gene, , on survival in glioblastoma.

BACKGROUND

The median survival for patients with glioblastoma (GBM), the most common primary malignant brain tumor in adults, has remained approximately 1 year for more than 2 decades. Recent advances in the field have identified GBM as a sexually dimorphic disease. It is less prevalent in females and they have better survival compared to males. The molecular mechanism of this difference has not yet been established. Iron is essential for many biological processes supporting tumor growth and its regulation is impacted by sex. Therefore, we interrogated the expression of a key component of cellular iron regulation, the (homeostatic iron regulatory) gene, on sexually dimorphic survival in GBM.

METHODS

We analyzed TCGA microarray gene expression and clinical data of all primary GBM patients (-wild type) to compare tumor mRNA expression of with overall survival, stratified by sex.

RESULTS

In low expressing tumors (below median expression, = 220), survival is modulated by both sex and MGMT status, with the combination of female sex and MGMT methylation resulting in over a 10-month survival advantage ( < .0001) over the other groups. Alternatively, expression of above the median (high , = 240) is associated with significantly worse overall survival in GBM, regardless of MGMT methylation status or patient sex. Gene expression analysis uncovered a correlation between high expression and expression of genes associated with immune function.

CONCLUSIONS

The level of expression in GBM has a sexually dimorphic impact on survival. Whereas expression below the median imparts a survival benefit to females, high expression is associated with significantly worse overall survival regardless of established prognostic factors such as sex or MGMT methylation.